AT393682B - METHOD FOR PRODUCING NEW 4H-DIOXINO- (4,5-C) -PYRIDINE DERIVATIVES - Google Patents

Description

AT 393 682 B

The invention relates to a process for the preparation of new 4H-dioxino (4,5-c) pyridine derivatives.

In particular, the invention relates to the preparation of 5- (1-cyano-1-alkyl-N-methyl-N-methoxyphenethyl) alkylamino-2,2,8-trimethyl-4H-dioxino- (4,5-c) - pyridine derivatives of the general formula (I)

where n is an integer between 2 and 5 inclusive, R j is a straight or branched lower alkyl to and R2 is two or three OCHg groups, and therapeutically acceptable salts of these compounds.

These compounds and their therapeutically acceptable salts are of interest as active ingredients for use in therapeutic compositions as calcium channel blockers. An investigation of the toxic properties has favorable LD ^ q values in rats and mice both per os and I.P. surrender.

According to the invention, the derivatives are obtained by reacting stoichiometric portions of corresponding 5- (1-cyano-1-Rj) methyl-2,2,8-trimethyl-4H-dioxino- (4,5-c) -pyridines of the formula (Π ), in which Rj has the meaning defined above, with the corresponding | N-methyl-N- (methoxy-phenethyl)] - a > -alkyl chloride of the formula (ΙΠ)

wherein n and R2 have the meaning defined above, easily obtained in the presence of a stoichiometric amount of sodium hydride in dimethyl sulfoxide at temperatures between 15 and 65 ° C.

In order to obtain the compounds II, the starting material is 5-hydroxymethyl-2,2,8-trimethyl-4H-dioxino- (4,5-c) -pyridine, as described in AT-B 303 729, which further chlorination with SOCI2 (gives 5-chloromethyl) and condensation with KCN (gives 5-cyanomethyl); the starting material II, d. H. 5- (1-Cyano) alkyl was prepared by treating the 5-cyanomethyl derivative with RjBr or R ^ Cl by the same procedure as further described for obtaining Compound I from Compounds II and III.

The following examples explain the invention in more detail, all temperatures were measured according to Tottoli.

Example 1 5- [l-Cyano-l-methyl-N-methyl-N- (3,4-dimethoxyphenethyl)] propylamino-2,2,8-trimethyl-4H-dioxino- (4,5-c) -pyridine n = 2 Rj = methyl R2 (OCH3) 2

After cleaning the apparatus with nitrogen, 4.9 g (0.1 mol) of 50% sodium hydride in oil and 100 ml of dimethyl sulfoxide were introduced into an 11 reactor which was provided with cooling, heating and stirring devices; -2-

AT 393 682 B the mixture was stirred and slowly a dropwise solution of 23.2 g (0.1 mol) of 5- (1-cyano) ethyl-2,2,8-trimethyl-4H-dioxino- ( 4,5-c) -pyridine, dissolved in 150 ml of dimethyl sulfoxide.

The reaction mixture turned dark and the temperature rose to 30 ° C. The mixture was stirred for 30 min and 25.8 g (0.1 mol) of [N-methyl-N- (3,4-dimethoxyphenethyl)] - 2-aminoethyl chloride, dissolved in 100 ml of dimethyl sulfoxide, were slowly added.

The reaction mixture was warmed to 50 ° C., stirred for 4 h, poured onto ice water and extracted with dichloromethylene. The organic phase was washed with water, separated, dried, treated with activated carbon, filtered and concentrated to dryness. The residue was treated with oxalic acid in 100 ml of acetone to give a yellow precipitate. This precipitate was washed separately and recrystallized from methyl ethyl ketone. Yield 38.6 g (71%) of a yellow crystalline product which melts at 164 ° C. The analysis showed perfect agreement with the formula C ^ H ^ N ^ O ^ C2H2O4.

Example 2 5- [l-Cyano-In-propyl-N-methyl-N- (3,4,5-trimethoxyphenethyl)] - n-propylamino-2,2,8-trimethyl-4H-dioxino- (4th , 5-c) -pyridine n = 2 Rj = n-propyl R2 = (OCH3) 3

The procedure of Example 1 was repeated using 5- (1-cyano) -n-butyl-2,2,8-trimethyl-4H-dioxino- (4,5-c) -pyridine and [N-methyl-N - (3,4,5-trimethoxy-phenethyl)] - 2-aminoethyl chloride at 40 ° C, was treated with hydrochloric acid. 32.5 g (59%) of a pale yellow powder melting at 204 ° C. were obtained. Analysis showed good agreement with the HCl formula.

Example 3 5- [1-Cyano-1-methyl-N-methyl-N- (3,4-dimethoxyphenethyl)] - n-butylamino-2,2,8-trimethyl-4H-dioxino- (4,5 -c) -pyridine n = 3 Rj = methyl R2 = (OCH3) 2

The procedure of Example 1 was repeated with the same pyridine derivative, but starting from [N-methyl-N- (3,4-dimethoxy-phenäthy 1)] -3-amino-n-propyl chloride at 55 ° C. The final treatment with acid was omitted. 29.5 g (63%) of a white product, melting at 176-178 ° C., were obtained. Analysis showed perfect agreement with the formula C ^ H ^ NgO ^

Example 4 5- [l-Cyano-l-ethyl-N-methyl-N- (3,4-dimethoxy-phenethyl)] - n-butylamino-2,2,8-trimethyl-4H-dioxino- (4,5 -c) - pyridine n = 3 Rj = ethyl R2 = (OCH3) 2

The procedure of Example 3 was repeated with 5- (l-cyano) -n-propyl-2,2,8-trimethyl-4H-dioxino- (4,5-c) -pyridine at 50 ° C. 25.2 g (52%) of a white powder, melting at 197-200 ° C., were obtained. Analysis showed

Example 5 5- [l-Cyano-1-isopropyl-N-methyl-N- (3,4-dimethoxyphenethyl)] - n-butylamino-2,2,8-trimethyMH-dioxino- (4,5-c ) -pyridine n = 3 Rj = isopropyl R2 = (OCH3) 2

The procedure of Example 3 was repeated using 5- (l-cyano-2-methyl) -n-propyl-2,2,8-trimethyl-4H-dioxino- (4,5-c) pyridine and the same amine chloride was assumed at 40 ° C, with an additional acid treatment with oxalic acid. 40.5 g (69%) of a white, crystalline powder, melting at 185-186 ° C., were obtained. Analysis showed perfect agreement with the formula C2H2O4. -3-

AT 393 682 B

Example 6 5- [l-Cyano-l-isopropyl-N-methyl-N- (3,4,5-trimethoxyphenethyl)] - n-butylamino-2,2,8-trimethyl-4H-dioxino- (4th , 5-c) -pyridine n = 3 Rj = isopropyl R2 = (OCH3) 3

The procedure of Example 5 was repeated using [N-methyl-N- (3,4,5-trimethoxyphenethyl)] - 3-aminopropyl chloride at 45 ° C. Another acid treatment was performed with oxalic acid. 45 g (73%) of a white, crystalline powder, melting at 170-173 ° C., were obtained. Analysis showed

, C2H204.

Example 7 5- [1-Cyano-In-butyl-N-methyl-N- (3,4,5-trimethoxyphenethyl)] - n-butylamino-2 ^, 8-trimethyl-4H-dioxino- (4, 5-c) pyridine n = 3 Rj = n-butyl R2 = (OCH3) 3

The procedure of Example 6 was repeated using 5- (l-cyano) -n-pentyl-2,2,8-trimethyl-4H-dioxino- (4,5-c) -pyridine and the same amine chloride at 60 ° C was assumed. 35.7 g (57%) of a white, crystalline powder, melting at 144-146 ° C., were obtained. Analysis showed good agreement with the formula C31H45N3 ° 5 'C2H2 ° 4-Example 8 5- [l-cyano-l-methyl-N-methyl-N- (3,4-dimethoxy-phenethyl)] - n-pentylamino-2 , 2,8-trimethyl-4H-dioxino- (4,5-c) -pyridine n = 4 Rj = methyl R2 = (OCH3) 2

The procedure of Example 3 was repeated, starting from the same pyridine derivative but starting from [N-methyl-N- (3,4-dimethoxy-phenethyl)] - 4-amino-n-butyl chloride at 65 ° C. 30.8 g (64%) of a white product, melting at 154-155 ° C., were obtained. Analysis showed good agreement with the formula C28H39N3 ° 4-Example 9 5- [l-cyano-In-pentyl-N-methyl-N- (3,4-dimethoxy-phenethyl)] - n-pentylamino-2,2,8 -trimethyl-4H-dioxino- (4,5-c) -pyridine n = 4 Rj = n-pentyl R2 = (OCH3) 2

The procedure of Example 8 was repeated, starting from 5- (l-cyano) -n-hexyl-2,2,8-trimethyl-4H-dioxino- (44-c) -pyridine and from the same amine chloride at 45 ° C with a final treatment with HG. 29.7 g (52%) of a white powder, melting at 167-169 ° C., were obtained. Analysis showed good agreement with the formula € 3 ^ 47 ^ () 4, HCl.

Example 10 5- [l-Cyano-l-ethyl-N-methyl-N- (3,4-dimethoxy-phenethyl)] - n-hexylamino-2,2,8-trimethyl-4H-dioxino- (4,5 -c) -pyridine n = 5 Rj = ethyl R2 = (OCH3) 2

The procedure of Example 4 was repeated, starting from the same pyridine derivative and from [N-methyl-N- (3,4-dimethoxy-phenethyl)] - 6-amino-n-pentyl chloride at 35 ° C. There were 23 ^ g (46%) of a pale yellow powder, melting at 193-197 ° C. Analysis showed good agreement with the formula C30H43N3 ° 4 * -4-

AT 393 682 B

Example 11 5- [l-Cyano-l-isopropyl-N-methyl-N- (3,4-dimethoxyphenethyl)] - n-hexylamino-2,2,8-trimethyl-4H-dioxino- (4,5 -c) -pyridine n = 5 Rj = isopropyl R2 = (OCH ^

The procedure of Example 10 was repeated using 5- (l-cyano-2-methyl) -n-propyl-2,2,8-trimethyl-4H-dioxino- (4,5-c) pyridine and the like Amine chloride was assumed at 30 ° C, was additionally treated with oxalic acid. Hs were obtained 39.6 g (65%) of a white, crystalline product, melting at 144 ° C. Analysis showed very good agreement with the formula

Example 12 5- [1-Cyano-In-butyl-N-methyl-N- (3,4,5-trimethoxyphenethyl)] - n-hexylamino-2,2,8-trimethyl-4H-dioxino- (4th , 5-c) -pyridine n = 5 Rj - n-butyl R2 = (OCHj) ^

The procedure of Example 7 was repeated, starting from | N-methyl-N- (3,4,5-trimethoxyphenethyl)] - 6-amino-n-pentyl chloride at 40 ° C, with a further treatment with oxalic acid . 38.1 g (58%) of a white, crystalline product melting at 131 ° C. were obtained. Analysis showed very good agreement with the formula C33H49N3O5, C2H2O4. toxicity

The LD ^ g values, determined by os, of the compounds obtained according to the invention, determined on mice, were 450 mg / kg and above. For comparison, the reference compound verapamil (DCI) has an LD ^ g value of 150 mg / kg. Cardiotoxicity in anesthetized dogs starts at 3 mg / kg IV while verapamil cardiotoxicity is 1 mg / kg

pharmacology

The importance of the compounds obtained according to the invention was determined by various tests. A) Isolated pieces of rabbit aorta, treated with various contracting agents.

This experiment was described according to the procedures by Furchgott R.F. and Bhadrakom S.-Reactions of strips of rabbit aorta to epinephrine, isopropylarterenol, sodium nitrite and other drugs; J. Pharmac. Exp. Therapeut, 1953, 108, 129-143, Van Rossum J.M., Arch. Int Pharacodyn. Ther., 1963, 143, 299-330 and Arunlakshana, O. and Schild, H.O., 1959, BriL J. Pharmac. 14.48-58, using norepinephrine (NE), serotonin (5-HT), histamine (HIST), KCl and angiotensin Π as agonists

The compounds obtained according to the invention were compared with verapamil in these agonists and showed a similar range of activity with significant and generally comparable values of PA2 (for NE, 5-HT and HIST) or of IC ^ g (for KCl or angiotensin); in any event, they appeared 5 to 10 times as active in 5-HT (average value for the compound according to the invention; 1.1 x 10 '^ and 7 x 10' ^ for verapamil). These compounds are potent 5-HT receptor antagonists. B) Experimental bumps induced by dimaprit 15 groups of five male Sprague Dawley rats (150-200 g) each were treated as follows;

Groups 1 to 12: The rats of each of the groups received 25 mg / kg per os of one of the compounds according to the invention, dissolved in 1 ml of physiological serum.

Groups 13 and 14: The rats of these groups received 1 ml of physiological serum.

Group 15: The rats in this group received 25 mg / kg ramitidine as a reference compound, dissolved in 1 ml physiological serum. 30 min after the administration, all groups except group 13, IP, received 175 mg / kg dimaprite (NH2- (CNH) - (CH2) 3 - N (CH3) 2).

Four hours after this treatment, the animals were sacrificed and the bumps counted. Group 13 was a blank control group and group 14 the bump control group. The results are given in percentages of protection compared to the dent control group. The protection for ramitidine is 39%, while the protection for the compounds obtained according to the invention is between 39 and 46.5%. -5-

Claims (2)

AT393 682 B Administration - Dosage For oral use, the compounds obtained according to the invention can be administered in 50 mg doses, in combination with a suitable diluent or carrier, as tablets, gelatin capsules or solutions. Dosage is 1 or 2 units a day. For IV administration, vials may contain 10 mg of active compound at a dose of 1 to 2 vials per day. Indications are headache, vasospasm and anxiety. PATENT CLAIM Process for the preparation of new 5- (l-cyano-l-alkyl-N-methyl-N-methoxyphenethyl) alkylamino-2,2,8-trimethyl-4H-dioxino- (4,5-c) -pyridine derivatives of the general Formula (Q, where n is an integer between 2 and 5 inclusive, Rj is a straight or branched lower alkyl to C5 and R2 is two or three OCH ^ groups, and therapeutically acceptable salts of these compounds by adding stoichiometric portions of the corresponding 5- ( l-Cyano-l-Rj) -methyl-2,2,8-trimethyl-4H-dioxino- (4,5-c) -pyridine of the formula (Π), in which Rj has the meaning defined above, with the corresponding [ N-methyl-N- (methoxy-phenethyl)] - tt> alkyl chloride of the formula (ΠΙ) (ID, in which n and R2 have the meaning defined above, in the presence of a stoichiometric amount of sodium hydride in dimethyl sulfoxide at temperatures between 15 and 65 ° C. CI (CH.) —N - CH, zn 4 CH, CH, -6- (III)